EP 477819 describes benzimidazol derivatives acting on potassium (BKCa) channels, useful for the treatment of e.g. convulsions, asthma, hypertension and ischaemia.
EP 617023 describes benzimidazole derivatives useful as openers of potassium channels, and in particular for the treatment of hypertension, coronary artery spasms, asthma, ischemia, irritable bowl syndrome, spastic bladder, psychosis and convulsions.
EP 747354 describes 3-substituted oxindole derivatives useful as maxi-K (BKCa) channel modulators.
Fox et al. [Fox A J, Barnes P J, Venkatesan P and Belvisi M G: Activation of Large Conductance Potassium Channels Inhibits the Afferent and Efferent Function of Airway Sensory Nerves in the Guinea Pig; J. Clin. Invest. 1997 99 (3) 513-519] have shown that NS 1619 (1,3-dihydro-1 -[2-hydroxy-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-2H-Benzimidazol-2-one), an opener of large conductance calcium-activated potassium (BKCa) channels, inhibits the activity of myelinated and no-myelinated sensory fibers innervating the guinea pig airways via activation of BKCa channels, and suggest that selective BKCa channel openers could be of benefit in the treatment of airway disease by reducing both local and central airway reflexes resulting from the excitation and sensitisation of sensory fibers by mediators released during inflammatory conditions. However this reference provides no indication of its usefulness in the treatment of obstructive or inflammatory airway diseases.
Owing to the restrictive transport properties of the brain microvasculature, which forms the blood-brain barrier (BBB) in vivo, transvascular delivery of therapeutic agents to brain tissue represents a particular obstacle, which must be taken into account in the development of therapeutics and routes by which these therapeutics are administered. One way of solving this problem is to apply a combination therapy, in which a vasoactive agent, e.g. the nanopeptide bradykinin or agonists or analogs thereof, is used to increase blood-brain barrier permeability in order to facilitate transport of a co-administered therapeutic agent.
Potassium channels are important regulators of blood vessel tone, and drugs acting on potassium channels have found use as vasoactive agents, which may also be used for facilitating transport of a co-administered therapeutic agent. Thus WO 01/54771 describes the use of potassium channel agonists for delivering a medicament to an abnormal brain region and/or malignant tumour. As only examples of potassium channel activators the compounds NS1619 (1,3-dihydro-1-[2-hydroxy-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-2H-benzimidazol-2-one), 1-EBIO (1-ethyl-2-benzimidazolione) and nitric oxide gas are used.